WO2017077488A1 - An inhalable fixed dose powder composition comprising glycopyrronium and formoterol - Google Patents

An inhalable fixed dose powder composition comprising glycopyrronium and formoterol Download PDF

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Publication number
WO2017077488A1
WO2017077488A1 PCT/IB2016/056637 IB2016056637W WO2017077488A1 WO 2017077488 A1 WO2017077488 A1 WO 2017077488A1 IB 2016056637 W IB2016056637 W IB 2016056637W WO 2017077488 A1 WO2017077488 A1 WO 2017077488A1
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pharmaceutically acceptable
composition
acceptable salt
μπι
range
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PCT/IB2016/056637
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French (fr)
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Ulhas Dhuppad
Sunil Chaudhari
Suresh RAJURKAR
Alkesh KASLIWAL
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Glenmark Pharmaceuticals Limited
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Publication of WO2017077488A1 publication Critical patent/WO2017077488A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules

Definitions

  • the present invention relates to an inhalable fixed dose powder composition comprising glycopyrronium or its pharmaceutically acceptable salt and formoterol or its pharmaceutically acceptable salt.
  • the present invention relates to an inhalable powder composition comprising effective amounts of glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt, and lactose; and; a process of preparing such composition and its use in the treatment of respiratory disorders.
  • Respiratory disorders related to airway inflammation include a number of lung diseases such as chronic obstructive pulmonary disease (COPD) and asthma.
  • COPD chronic obstructive pulmonary disease
  • Asthma is a disease characterized by an increased responsiveness of the trachea and bronchi to various stimuli, and manifested by widespread narrowing of the airways that changes in severity either spontaneously or as a result of treatment.
  • the events leading to airway obstruction in asthma include edema of airway walls, infiltration of inflammatory cells into the lung, production of various inflammatory mediators and increased mucous production.
  • the current therapy for asthma includes bronchodilator drugs, corticosteroids and leukotriene antagonists.
  • Bronchodilator drugs dilate the bronchi and bronchioles, decreasing resistance in the respiratory airway and increasing airflow to the lungs.
  • Corticosteroid drugs are effective at reducing asthma symptoms by blocking the body's inflammatory response.
  • the leukotriene antagonists have limited efficacy, with only small increases in pulmonary function demonstrated in clinical trials.
  • COPD is a term used to classify two major airflow obstruction disorders: chronic bronchitis and emphysema.
  • Chronic bronchitis is inflammation of the bronchial airways.
  • Emphysema is inflammation of the alveoli, or air sacs in the lungs. Emphysema has a number of causes, including smoking, exposure to environmental pollutants, alpha-one antitrypsin deficiency, and aging.
  • COPD is a disease of the respiratory apparatus, characterized by an irreversible obstruction of the airways, of a degree that varies according to the gravity.
  • Glycopyrronium is a long acting muscarinic antagonist. Its chemical name is 3-(2- cyclopentyl-2-hydroxy-2-phenylacetoxy)- 1 , 1-dimethylpyrrolidinium. It has following structure:
  • Glycopyrronium bromide (also known as Glycopyrrolate) is currently approved in the U.S. as Robinul (as 0.2mg/ml injection and as tablets of lmg strength); which is indicated for treatment of peptic ulcer and as preoperative anti-muscarinic to reduce salivary, tracheobronchial, and pharyngeal secretions in anesthesia.
  • Glycopyrronium bromide is also approved in Europe as dry powder inhaler Seebri Breezhaler (Novartis) which is indicated for the treatment of COPD. Seebri Breezhaler is presented as an inhalation powder in hard capsules. Each capsule contains 63 meg of glycopyrronium bromide, equivalent to 50 meg of glycopyrronium.
  • SeebriTM Neohaler ® glycopyrrolate inhalation powder 15.6 meg as a stand-alone monotherapy for the same COPD indication.
  • SeebriTM Neohaler and Seebri Breezhaler ® contains lactose and magnesium stearate as inactive ingredients.
  • Formoterol N-[2-hydroxy-5-[ l-hydroxy-2-[ l-(4-methoxyphenyl) propan-2- ylamino] ethyl]phenyl]formamide
  • COPD chronic obstructive pulmonary disease
  • WO 2011/076841 discloses solution aerosol formulation suitable for administering to COPD patients by means of a pressurized metered dose inhaler, comprising glycopyrronium chloride in combination with formoterol
  • WO2010/138868 relates to a pharmaceutical formulation comprising suspension medium comprising combination of long acting muscarinic antagonist and beta agonist to form co-suspension
  • the present invention relates to an inhalable fixed dose dry powder composition
  • an inhalable fixed dose dry powder composition comprising glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt and lactose.
  • an inhalable fixed dose dry powder composition comprising glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt and lactose; wherein said composition is free from a hydrophobic excipient.
  • an inhalable fixed dose dry powder composition consisting of effective amounts of glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt and lactose.
  • the present invention relates to an inhalable fixed dose dry powder composition
  • a co-micronized premix consisting of glycopyrronium or its pharmaceutically acceptable salt and one part of lactose in a weight ratio of about 1 : 10 to about 1 :500 and having D90 particle size in the range of about 0.5 ⁇ to about 10 ⁇ ; (ii) formoterol or its pharmaceutically acceptable salt; and (iii) another part of lactose having D90 particle size in the range of about 5 ⁇ to about 300 ⁇ ; wherein said composition is free from a hydrophobic excipient.
  • the weight ratio of glycopyrronium or its pharmaceutically acceptable salt to the one part of lactose in the co-micronized premix ranges from about 1 :60 to about 1 :400.
  • the present invention relates to an inhalable fixed dose dry powder composition
  • a co-micronized premix consisting of glycopyrronium or its pharmaceutically acceptable salt and one part of lactose in a weight ratio of about 1 :50 to about 1 :500 and having D9090 particle size in the range of about 0.5 ⁇ to about 10 ⁇ ; (ii) formoterol or its pharmaceutically acceptable salt; and (iii) another part of lactose having D90 particle size in the range of about 5 ⁇ to about 300 ⁇ ; wherein said composition is free from a hydrophobic excipient.
  • the weight ratio of glycopyrronium or its pharmaceutically acceptable salt to the one part of lactose in the co-micronized premix ranges from about 1 :60 to about 1 :400.
  • the present invention relates to an inhalable fixed dose dry powder composition
  • a co-micronized premix consisting of glycopyrronium or its pharmaceutically acceptable salt and one part of lactose in a weight ratio of about 1 :50 to about 1 :500 and having D90 particle size in the range of about 0.5 ⁇ to about 10 ⁇ ; (ii) formoterol or its pharmaceutically acceptable salt; and (iii) another part of lactose having D90 particle size in the range of about 5 ⁇ to about 200 ⁇ ; wherein said composition is free from a hydrophobic excipient.
  • the weight ratio of glycopyrronium or its pharmaceutically acceptable salt to the one part of lactose in the co-micronized premix ranges from about 1:70 to about 1:300, or from about
  • the present invention relates to an inhalable fixed dose dry powder composition (i) a co-micronized premix consisting of glycopyrronium or its pharmaceutically acceptable salt and one part of lactose in a weight ratio of about 1: 100 to about 1:200 and having D90 particle size in the range of about 1 ⁇ to about 8 ⁇ ; (ii) formoterol or its pharmaceutically acceptable salt; and (iii) another part of lactose having
  • D9090 particle size in the range of about 8 ⁇ to about 200 ⁇ ; wherein said composition is free from a hydrophobic excipient.
  • the D90 particle size of the co- micronized premix is in the range of about 2 ⁇ to about 7 ⁇ , or about 3 ⁇ to about 5 ⁇ .
  • the D90 particle size of the co-micronized premix is in the range of about 2 ⁇ to about 7 ⁇ , or about 3 ⁇ to about 6 ⁇ .
  • said inhalable pharmaceutical dry powder composition is free from a hydrophobic excipient.
  • step (b) blending the co-micronized premix of step (a) and formoterol or its pharmaceutically acceptable salt with another part of lactose having D90 particle size in the range of about 5 ⁇ to about 200 ⁇ .
  • step (a) co-micronising glycopyrronium or its pharmaceutically acceptable salt with one part of lactose in a weight ratio of about 1:50 to about 1:500 to obtain a micronized premix having D90 particle size less than about 5 ⁇ ; and (b) blending the co-micronized premix of step (a) and formoterol or its pharmaceutically acceptable salt with another part of lactose having D90 particle size in the range of about 8 ⁇ to about 200 ⁇ .
  • step (b) blending the co-micronized premix of step (a) and formoterol or its pharmaceutically acceptable salt with another part of lactose having D90 particle size in the range of about 8 ⁇ to about 200 ⁇ .
  • the weight ratio of glycopyrronium or its pharmaceutically acceptable salt to lactose in the co-micronized premix of the present invention ranges from about 1: 10 to about 1 :500, from about 1:50 to about 1 :500, from about 1 :70 to about 1:300, more preferably from about 1 : 100 to about 1: 200.
  • the weight ratio of the co-micronized premix to lactose ranges froml: l to 1 :50, preferably, from 1 :5 to 1:30.
  • an inhalable fixed dose dry powder composition comprising from about 0.01% to about 10% by weight of glycopyrronium or its pharmaceutically acceptable salt, and about 0.01% to about 10% by weight of formoterol or its pharmaceutically acceptable salt wherein the composition has fine particle mass (FPM) in the range of 1 meg to 15 meg; and wherein said composition is prepared by a method comprising:
  • an inhalable fixed dose dry powder composition comprising from about 0.01% to about 10% by weight of glycopyrronium or its pharmaceutically acceptable salt, and about 0.01% to about 10% by weight of formoterol or its pharmaceutically acceptable salt wherein the composition has total fine particle mass (FPM) in the range of 1 meg to 10 meg; and wherein said composition is prepared by a method comprising:
  • step (b) blending the co-micronized premix of step (a), and formoterol or its pharmaceutically acceptable salt with another part of lactose having D90 particle size in the range of about 8 ⁇ to about 200 ⁇ .
  • an inhalable fixed dose dry powder composition comprising from about 0.01% to about 10% by weight of glycopyrronium or its pharmaceutically acceptable salt, and about 0.01% to about 10% by weight of formoterol or its pharmaceutically acceptable salt wherein the composition has fine particle mass (FPM) for Glycopyrronium in the range of 2.5 meg to 9 meg; and wherein said composition is prepared by a method comprising:
  • step (b) blending the co-micronized premix of step (a), and formoterol or its pharmaceutically acceptable salt with another part of lactose having D90 particle size in the range of about 8 ⁇ to about 300 ⁇ .
  • an inhalable fixed dose dry powder composition comprising a co-micronized premix consisting of glycopyrronium or its pharmaceutically acceptable salt and lactose in a weight ratio of about 1: 100 to about 1:200; formoterol or its pharmaceutically acceptable salt and lactose wherein said premix has mean particle size of less than about 5 ⁇ ; and said composition is free from a hydrophobic excipient; and wherein the composition has total fine particle mass in the range of 1 meg to 15 meg.
  • an inhalable fixed dose dry powder composition comprising (a) glycopyrronium bromide in an amount of 5 meg to 50 meg, (b) formoterol fumarate dihydrate in an amount of 5 meg to 50 meg and (c) lactose wherein said composition is free from magnesium stearate.
  • an inhalable fixed dose dry powder composition comprising an effective amount of glycopyrronium or its pharmaceutically acceptable salt; formoterol or its pharmaceutically acceptable salt and lactose wherein the said composition has a Hausner ratio in the range of 1 to 2 or preferably, the Hausner ratio is in the range of 1.25 to 1.75 or more preferably, the Hausner ratio is in the range of 1.30 to 1.65.
  • an inhalable fixed dose dry powder composition comprising an effective amount of glycopyrronium or its pharmaceutically acceptable salt; formoterol or its pharmaceutically acceptable salt and lactose wherein said composition has a Carr index in the range of 20% -45% or more preferably, the Carr index is in the range of 22%-40%.
  • an inhalable fixed dose dry powder composition comprising an effective amount of glycopyrronium or its pharmaceutically acceptable salt; formoterol or its pharmaceutically acceptable salt and lactose; wherein said composition has a bulk density in the range of 0.45 g/mL - 0.65 g/mL or more preferably the bulk density in the range of 0.5 g/mL - 0.6 g/mL.
  • an inhalable fixed dose dry powder composition comprising an effective amount of glycopyrronium or its pharmaceutically acceptable salt; formoterol or its pharmaceutically acceptable salt and lactose wherein said composition has a tap density in the range of 0.55 g/mL - 0.95 g/mL or more preferably the tap density in the range of 0.6 g/mL - 0.9 g/mL.
  • the present invention relates to a method of treating respiratory disorders in a subject;, said method comprising administering by inhalation route to the subject fixed dose dry powder composition comprising effective amounts of glycopyrronium bromide, formoterol fumarate dihydrate and lactose, wherein the said composition is free from magnesium stearate.
  • the respiratory disorder in the context of present invention, includes but is not limited to asthma, emphysema, bronchitis, COPD, sinusitis, respiratory depression, reactive airways dysfunction syndrome (RADS), acute respiratory distress syndrome (ARDS), irritant induced asthma, occupational asthma, sensory hyper-reactivity, airway (or pulmonary) inflammation, multiple chemical sensitivity, and aid in smoking cessation therapy.
  • asthma includes acute asthma, chronic asthma, intermittent asthma, mild persistent asthma, moderate persistent asthma, severe persistent asthma, chronic persistent asthma, mild to moderate asthma, mild to moderate persistent asthma, mild to moderate chronic persistent asthma, allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, nocturnal asthma, bronchial asthma, exercise induced asthma, occupational asthma, seasonal asthma, silent asthma, gastroesophageal asthma, idiopathic asthma and cough variant asthma.
  • the present invention relates to a method of treating asthma in a subject, said method comprising administering by inhalation route to the subject the dry powder composition comprising an effective amount of glycopyrronium bromide, formoterol fumarate dihydrate and lactose; wherein said composition is free from magnesium stearate.
  • the present invention relates to a method of treating COPD in a subject, said method comprising administering by inhalation route to the subject the dry powder composition comprising an effective amount of glycopyrronium bromide, formoterol fumarate dihydrate and lactose; wherein said composition is free from magnesium stearate.
  • the present invention relates to use of an effective amount of glycopyrronium bromide and formoterol fumarate dihydrate in the fixed dose inhalable pharmaceutical dry powder composition of the present invention for the treatment of respiratory disorders in a subject.
  • the present invention relates to fixed dose inhalable pharmaceutical dry powder composition
  • a fixed dose inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium bromide and formoterol fumarate dihydrate for the treatment of respiratory disorders in a subject.
  • an excipient includes a single excipient as well as two or more different excipients, and the like.
  • Glycopyrrolate is a quaternary ammonium salt.
  • Suitable counter ions are pharmaceutically acceptable counter ions including, for example, fluoride, chloride, bromide, iodide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, propionate, butyrate, lactate, citrate, tartrate, malate, maleate, succinate, benzoate, p-chlorobenzoate, diphenyl- acetate or triphenylacetate, o-hydroxybenzoate, p-hydroxybenzoate, 1- hydroxynaphthalene-2-carboxylate, 3-hydroxynaphthalene-2-carboxylate, methane- sulfonate and benzenesulfonate.
  • glycopyrronium bromide is glycopyrronium bromide.
  • Glycopyrrolate has two centers of asymmetry (chiral centers), and can exist in four stereoisometric forms namely (3R, 2'R)-, (3S, 2'R)-, (3R, 2'S)- and (3S, 2'S).
  • salts and esters are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit to risk ratio, and effective for their intended use.
  • Representative acid additions salts include the hydrochloride, furoate, hydrobromide, sulphate, bisulphate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate, succinate, tartrate, ascorbate, glucoheptonate, lactobionate, and lauryl sulphate salts.
  • Representative alkali or alkaline earth metal salts include the sodium, calcium, potassium and magnesium salts.
  • glycol is used in a broad sense to include not only “formoterol” per se but also its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable esters, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable complex, pharmaceutically acceptable co-crystals etc.
  • formoterol salts include acid addition salts such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid and p-toluenesulfonic.
  • the formoterol salt used in the present invention is formoterol tartrate or formoterol fumarate, more preferably formoterol fumarate dihydrate.
  • an effective amount denotes an amount of an active ingredient that, when administered to a subject for treating respiratory disorders, produces an intended therapeutic benefit in a subject.
  • active ingredient (used interchangeably with “active” or “active substance” or “drug”) as used herein includes Glycopyrronium or a pharmaceutically acceptable salt thereof.
  • treating also covers the prophylaxis, mitigation, prevention, amelioration, or suppression of a disorder modulated by the Glycopyrronium or its pharmaceutically acceptable salt in a mammal.
  • subject includes mammals like human and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).
  • domestic animals e.g., household pets including cats and dogs
  • non-domestic animals such as wildlife
  • the subject is a human.
  • pharmaceutically acceptable excipients any of the components of a pharmaceutical composition other than the actives and which are approved by regulatory authorities or are generally regarded as safe for human or animal use.
  • the term "average particle size” refers to the distribution of particles, wherein about 50 volume percent of all the particles measured have a size less than the defined average particle size value and about 50 volume percent of all measurable particles measured have a particle size greater than the defined average particle size value. This can be identified by the term “D50” or “d (0.5)”.
  • D90 value relates to about 90 volume percent of all the particles measured have a size less than the defined particle size value (also referred to as "D90 particle size').
  • the particle size can be measured using various techniques like laser diffraction, photon correlation spectroscopy (PCS) and Coulter's principle.
  • co-micronisation refers to milling or micronisation of the active ingredient and lactose together in suitable mill to obtain micronised mixture of active ingredient and lactose.
  • the mixture of active ingredient and lactose after co-micronisation process can be called as co-micronised premix of active ingredient and lactose.
  • Jet mill, Air jet mill, Ball mill and the like can be used for the milling purpose.
  • Air Jet Mill may be used for co-micronisation.
  • the fine particle mass (FPM) test is normally conducted using a validated multistage impactor or impinger method, or a suitably validated alternative. It is normally considered acceptable to set upper and lower limits on the results of pooled stages corresponding to a particle size distribution of less than 5 micrometer, although alternative limits may be found acceptable with adequate justification.
  • the drug mass should be reported rather than the percentage of emitted dose (or other derived parameter).
  • the Mass Median Aerodynamic Diameter is defined as the diameter at which 50% of the particles by mass are larger and 50% are smaller.
  • the Carr index and Hausner ratio are frequently used in as an indication of the flowability of a powder.
  • the Carr index and Hausner ratio can be determined using Tap Density Apparatus.
  • the bulk density and tap density of the powder composition can be determined by Tap density apparatus.
  • composition in the above embodiments may optionally comprise one or more pharmaceutically acceptable excipients.
  • the inhalable pharmaceutical dry powder composition of the present invention may contain one or more pharmaceutically acceptable excipients.
  • excipients include but are not limited to diluents, solvents, and the like.
  • the pharmaceutically acceptable diluent suitable for use in the invention is selected from lactose, mannitol, sucrose, trehalose, cyclodextrin, or mixtures thereof.
  • the pharmaceutically acceptable diluent is lactose.
  • Various grade of lactose are available for use in dry powder compositions are selected from Respitose SV010, Respitose ® SV003, Respitose ® ML006, InhaLac 70, InhaLac 230, Lactose Monohydrate Inhalation 40M, Lactose Anhydrous 120M, Lactohale ® 300, and the like.
  • solvents examples include water, propylene glycol, ether, petroleum ether, alcohols, e.g. methanol, ethanol, isopropyl alcohol and higher alcohols; alkanes, e.g. pentane, hexane and heptane; ketones, e.g. acetone and methyl ethyl ketone; and the like and mixtures thereof.
  • step (b) blending the co-micronized premix of step (a); formoterol or its pharmaceutically acceptable salt with another part of lactose having D90 particle size in the range of about 8 ⁇ to about 200 ⁇ .
  • the powder composition may be further be filled into a capsule for inhalation or may be processed into a lightly compressed tablet or powder agglomeration which can be easily crushed to obtain a powder for inhalation.
  • the composition can be filled, either as discrete dosage units, in a blister or a sachet or in a reservoir for multiple uses.
  • an inhalable fixed dose dry powder composition comprising glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt and lactose; wherein said composition is free from a hydrophobic excipient.
  • the co-micronization followed by blending is preferred over simple blending process.
  • an inhalable fixed dose dry powder composition consisting of an effective amount of glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt and lactose.
  • the present invention relates to an inhalable fixed dose dry powder composition comprising (i) a co-micronized premix consisting of glycopyrronium or its pharmaceutically acceptable salt and one part of lactose in a weight ratio of about 1 : 10 to about 1 :500 and having D90 particle size in the range of about 0.5 ⁇ to about 10 ⁇ ; (ii) formoterol or its pharmaceutically acceptable salt; and (iii) another part of lactose having D90 particle size in the range of about 5 ⁇ to about 300 ⁇ ; wherein said composition is free from a hydrophobic excipient.
  • the weight ratio of glycopyrronium or its pharmaceutically acceptable salt to the one part of lactose in the co-micronized premix ranges from about 1 :60 to about 1 :400
  • the present invention relates to an inhalable fixed dose dry powder composition
  • an inhalable fixed dose dry powder composition comprising; (i) a co-micronized premix consisting of glycopyrronium or its pharmaceutically acceptable salt and one part of lactose in a weight ratio of about 1 :50 to about 1 :500 and having D90 particle size in the range of about 0.5 ⁇ to about 10 ⁇ ; (ii) formoterol or its pharmaceutically acceptable salt; and (iii) another part of lactose having D90 particle size in the range of about 5 ⁇ to about 200 ⁇ ; wherein said composition is free from a hydrophobic excipient.
  • the weight ratio of glycopyrronium or its pharmaceutically acceptable salt to the one part of lactose in the co-micronized premix ranges from about 1 :70 to about 1 :300, or from about 1 : 100 to about 1 :200.
  • the present invention relates to an inhalable fixed dose dry powder composition (i) a co-micronized premix consisting of glycopyrronium or its pharmaceutically acceptable salt and one part of lactose in a weight ratio of about 1 : 100 to about 1 :200 and having D90 particle size in the range of about 1 ⁇ to about 8 ⁇ ; (ii) formoterol or its pharmaceutically acceptable salt; and (iii) another part of lactose having D90 particle size in the range of about 8 ⁇ to about 200 ⁇ ; wherein said composition is free from a hydrophobic excipient.
  • the D90 particle size of the co-micronized premix is in the range of about 2 ⁇ to about 7 ⁇ , or about 3 ⁇ to about 5 ⁇ .
  • said inhalable pharmaceutical dry powder composition is free from a hydrophobic excipient.
  • the present invention relates to an inhalable fixed dose dry powder composition
  • a co-micronized premix consisting of glycopyrronium or its pharmaceutically acceptable salt and one part of lactose in a weight ratio of about 1 :50 to about 1 :500 and having D90 particle size in the range of about 0.5 ⁇ to about 10 ⁇ ; (ii) formoterol or its pharmaceutically acceptable salt; and (iii) another part of lactose having D90 particle size in the range of about 5 ⁇ to about 300 ⁇ ; wherein said composition is free from a hydrophobic excipient.
  • the weight ratio of glycopyrronium or its pharmaceutically acceptable salt to the one part of lactose in the co-micronized premix ranges from about 1 :60 to about 1 :400.
  • step (b) blending the co-micronized premix of step (a) and formoterol or its pharmaceutically acceptable salt with another part of lactose having D90 particle size in the range of about 5 ⁇ to about 200 ⁇ .
  • step (b) blending the co-micronized premix of step (a) and formoterol or its pharmaceutically acceptable salt with another part of lactose having D90 particle size in the range of about 8 ⁇ to about 200 ⁇ .
  • a process for preparing an inhalable fixed dose dry powder composition comprising glycopyrronium or its pharmaceutically acceptable salt and formoterol or its pharmaceutically acceptable salt; wherein said process comprises: (a) co-micronising glycopyrronium or its pharmaceutically acceptable salt with one part of lactose in a weight ratio of about 1 : 100 to about 1 :200 to obtain a micronized premix having D90 particle size less than about 5 ⁇ ; and;
  • step (b) blending the co-micronized premix of step (a) and formoterol or its pharmaceutically acceptable salt with another part of lactose having D90 particle size in the range of about 8 ⁇ to about 200 ⁇ .
  • the weight ratio of glycopyrronium or its pharmaceutically acceptable salt to lactose in the co-micronized premix of the present invention ranges from about 1 : 10 to about 1 :500, 1 :50 to about 1 :500, from about 1 :70 to about 1 :300, more preferably from about 1 : 100 to about 1 : 200.
  • the weight ratio of the co-micronized premix to lactose ranges froml : l to 1 :50, preferably, from 1 :5 to 1 :30.
  • an inhalable fixed dose dry powder composition comprising from about 0.01 % to about 10% by weight of glycopyrronium or its pharmaceutically acceptable salt, and about 0.01 % to about 10% by weight of formoterol or its pharmaceutically acceptable salt wherein the composition has fine particle mass (FPM) in the range of 1 meg to 15 meg; and wherein said composition is prepared by a method comprising:
  • step (b) blending the co-micronized premix of step (a), and formoterol or its pharmaceutically acceptable salt with another part of lactose having D90 particle size in the range of about 8 ⁇ to about 200 ⁇ .
  • an inhalable fixed dose dry powder composition comprising from about 0.01 % to about 10% by weight of glycopyrronium or its pharmaceutically acceptable salt, and about 0.01 % to about 10% by weight of formoterol or its pharmaceutically acceptable salt wherein the composition has total fine particle mass (FPM) in the range of 1 meg to 10 meg; and wherein said composition is prepared by a method comprising: (a) co-micronising glycopyrronium or its pharmaceutically acceptable salt with one part of lactose to obtain a micronized premix having D90 particle size less than about 5 ⁇ ; and;
  • step (b) blending the co-micronized premix of step (a), and formoterol or its pharmaceutically acceptable salt with another part of lactose having D90 particle size in the range of about 8 ⁇ to about 200 ⁇ .
  • an inhalable fixed dose dry powder composition comprising from about 0.01% to about 10% by weight of glycopyrronium or its pharmaceutically acceptable salt, and about 0.01% to about 10% by weight of formoterol or its pharmaceutically acceptable salt wherein the composition has fine particle mass (FPM) for Glycopyrronium in the range of 2.5 meg to 9 meg; and wherein said composition is prepared by a method comprising:
  • step (b) blending the co-micronized premix of step (a), and formoterol or its pharmaceutically acceptable salt with another part of lactose having D90 particle size in the range of about 8 ⁇ to about 300 ⁇ .
  • an inhalable fixed dose dry powder composition comprising a co-micronized premix consisting of glycopyrronium or its pharmaceutically acceptable salt and lactose in a weight ratio of about 1: 100 to about 1:200; formoterol or its pharmaceutically acceptable salt and lactose wherein said premix has mean particle size of less than about 5 ⁇ ; and said composition is free from a hydrophobic excipient; and wherein the composition has total fine particle mass in the range of 1 meg to 10 meg.
  • an inhalable fixed dose dry powder composition comprising (a) glycopyrronium bromide in an amount of 5 meg to 50 meg, (b) formoterol fumarate dihydrate in an amount of 5 meg to 50 meg and (c) lactose wherein said composition is free from magnesium stearate.
  • an inhalable fixed dose dry powder composition comprising an effective amount of glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt and lactose wherein the said composition has a Hausner ratio in the range of 1 to 2 or preferably, the Hausner ratio is in the range of 1.25 to 1.75 or more preferably, the Hausner ratio is in the range of 1.30 to 1.65.
  • an inhalable fixed dose dry powder composition comprising an effective amount of glycopyrronium or its pharmaceutically acceptable salt; formoterol or its pharmaceutically acceptable salt and lactose wherein said composition has a Carr index in the range of 20% -45% or more preferably, the Carr index is in the range of 22%-40%.
  • an inhalable fixed dose dry powder composition comprising an effective amount of glycopyrronium or its pharmaceutically acceptable salt; formoterol or its pharmaceutically acceptable salt and lactose wherein said composition has a bulk density in the range of 0.45 g/mL - 0.65 g/mL or more preferably the bulk density in the range of 0.5 g/mL - 0.6 g/mL.
  • an inhalable fixed dose dry powder composition comprising an effective amount of glycopyrronium or its pharmaceutically acceptable salt; formoterol or its pharmaceutically acceptable salt and lactose wherein said composition has a tap density in the range of 0.55 g/mL - 0.95 g/mL or more preferably the tap density in the range of 0.6 g/mL - 0.9 g/mL.
  • an inhalable fixed dose dry powder composition comprising from about 0.01% to about 10%, preferably from about 0.02% to about 5%, more preferably from about 0.03% to about 4% by weight of glycopyrronium or its pharmaceutically acceptable salt, and about 0.01% to about 10% by weight of formoterol or its pharmaceutically acceptable salt
  • the present invention relates to a method of treating respiratory disorders in a subject, said method comprising administering by inhalation route to the subject fixed dose dry powder composition comprising effective amounts of glycopyrronium bromide, formoterol fumarate dihydrate and lactose, wherein said composition is free from magnesium stearate.
  • the respiratory disorder in the context of present invention, includes but is not limited to asthma, emphysema, bronchitis, COPD, sinusitis, respiratory depression, reactive airways dysfunction syndrome (RADS), acute respiratory distress syndrome (ARDS), irritant induced asthma, occupational asthma, sensory hyper-reactivity, airway (or pulmonary) inflammation, multiple chemical sensitivity, and aid in smoking cessation therapy.
  • asthma includes acute asthma, chronic asthma, intermittent asthma, mild persistent asthma, moderate persistent asthma, severe persistent asthma, chronic persistent asthma, mild to moderate asthma, mild to moderate persistent asthma, mild to moderate chronic persistent asthma, allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, nocturnal asthma, bronchial asthma, exercise induced asthma, occupational asthma, seasonal asthma, silent asthma, gastroesophageal asthma, idiopathic asthma and cough variant asthma.
  • the present invention relates to a method of treating asthma in a subject, said method comprising administering by inhalation route to the subject the dry powder composition comprising an effective amount of glycopyrronium bromide, formoterol fumarate dihydrate and lactose; wherein said composition is free from magnesium stearate.
  • the present invention relates to a method of treating COPD in a subject, said method comprising administering by inhalation route to the subject the dry powder composition comprising an effective amount of glycopyrronium bromide, formoterol fumarate dihydrate and lactose; wherein said composition is free from magnesium stearate.
  • the present invention relates to use of an effective amount of glycopyrronium bromide; formoterol fumarate dihydrate in the inhalable pharmaceutical dry powder composition of the present invention for the treatment of respiratory disorders in a subject.
  • the present invention relates to an inhalable dry powder composition
  • an inhalable dry powder composition comprising an effective amount of glycopyrronium bromide; formoterol fumarate dihydrate for the treatment of respiratory disorders in a subject.
  • step 1 was sifted with a part of coarse grade lactose monohydrate and then mixed in a suitable blender. 3.
  • step 2 was sifted with remaining part of lactose and then mixed in a suitable blender.
  • step 3 The blend of step 3 was filled in a capsule.
  • Lactose monohydrate was divided in two parts.
  • Glycopyrrolate was mixed with first part of Lactose Monohydrate (Respitose SVOlO), and sifted through #60 sieve and blended.
  • Glycopyrrolate micronised premix formoterol fumarate dihydrate and fine grade lactose (Respitose ML006) were sifted and then mixed in a suitable blender.
  • step 2 The blend of step 1 was sifted with a part of coarse grade lactose monohydrate and then mixed in a suitable blender.
  • step 2 The blend of step 2 was sifted with remaining part of lactose and then mixed in a suitable blender.
  • step 3 The blend of step 3 was filled in a capsule.

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Abstract

The present invention relates to an inhalable fixed dose powder composition comprising glycopyrronium or its pharmaceutically acceptable salt and formoterol or its pharmaceutically acceptable salt. Preferably, the present invention relates to an inhalable powder composition comprising effective amounts of glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt, and lactose; and; a process of preparing such composition and its use in the treatment of respiratory disorders.

Description

AN INHALABLE FIXED DOSE POWDER COMPOSITION COMPRISING GLYCOPYRRONIUM AND FORMOTEROL
PRIORITY DOCUMENT
This patent application claims priority to Indian Provisional Patent Application number 4196/MUM/2015 (filed on Nov 04, 2015), the contents of which are incorporated by reference herein.
TECHNICAL FIELD OF THE INVENTION
The present invention relates to an inhalable fixed dose powder composition comprising glycopyrronium or its pharmaceutically acceptable salt and formoterol or its pharmaceutically acceptable salt. Preferably, the present invention relates to an inhalable powder composition comprising effective amounts of glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt, and lactose; and; a process of preparing such composition and its use in the treatment of respiratory disorders.
BACKGROUND OF THE INVENTION
Respiratory disorders related to airway inflammation include a number of lung diseases such as chronic obstructive pulmonary disease (COPD) and asthma.
Asthma is a disease characterized by an increased responsiveness of the trachea and bronchi to various stimuli, and manifested by widespread narrowing of the airways that changes in severity either spontaneously or as a result of treatment. The events leading to airway obstruction in asthma include edema of airway walls, infiltration of inflammatory cells into the lung, production of various inflammatory mediators and increased mucous production.
The current therapy for asthma includes bronchodilator drugs, corticosteroids and leukotriene antagonists. Bronchodilator drugs dilate the bronchi and bronchioles, decreasing resistance in the respiratory airway and increasing airflow to the lungs. Corticosteroid drugs are effective at reducing asthma symptoms by blocking the body's inflammatory response. The leukotriene antagonists have limited efficacy, with only small increases in pulmonary function demonstrated in clinical trials.
COPD is a term used to classify two major airflow obstruction disorders: chronic bronchitis and emphysema. Chronic bronchitis is inflammation of the bronchial airways. Emphysema is inflammation of the alveoli, or air sacs in the lungs. Emphysema has a number of causes, including smoking, exposure to environmental pollutants, alpha-one antitrypsin deficiency, and aging. COPD is a disease of the respiratory apparatus, characterized by an irreversible obstruction of the airways, of a degree that varies according to the gravity.
Glycopyrronium is a long acting muscarinic antagonist. Its chemical name is 3-(2- cyclopentyl-2-hydroxy-2-phenylacetoxy)- 1 , 1-dimethylpyrrolidinium. It has following structure:
Figure imgf000003_0001
(Glycopyrronium)
Glycopyrronium bromide (also known as Glycopyrrolate) is currently approved in the U.S. as Robinul (as 0.2mg/ml injection and as tablets of lmg strength); which is indicated for treatment of peptic ulcer and as preoperative anti-muscarinic to reduce salivary, tracheobronchial, and pharyngeal secretions in anesthesia. Glycopyrronium bromide is also approved in Europe as dry powder inhaler Seebri Breezhaler (Novartis) which is indicated for the treatment of COPD. Seebri Breezhaler is presented as an inhalation powder in hard capsules. Each capsule contains 63 meg of glycopyrronium bromide, equivalent to 50 meg of glycopyrronium. The FDA has recently approved Seebri™ Neohaler® (glycopyrrolate) inhalation powder 15.6 meg as a stand-alone monotherapy for the same COPD indication. Seebri™ Neohaler and Seebri Breezhaler® contains lactose and magnesium stearate as inactive ingredients.
Formoterol (N-[2-hydroxy-5-[ l-hydroxy-2-[ l-(4-methoxyphenyl) propan-2- ylamino] ethyl]phenyl]formamide) is a long long-acting p2-agonist used in the management of asthma and/or chronic obstructive pulmonary disease (COPD).
Figure imgf000004_0001
(Formoterol)
It is commercially available in US as metered dose inhaler marketed as Symbicort® and Dulera® in combination with budesonide and mometasone respectively. It is also commercially available in US as nebuliser and dry powder inhaler.
International Patent Application Publication No. WO 01/76575 describes a pharmaceutical composition for pulmonary delivery comprising glycopyrrolate in a controlled release formulation.
International Patent Application Publication No. WO2005/107873 relates to the use of glycopyrronium in treatment of childhood asthma.
International Patent Application Publication No. WO 2005/105043 relates to dry powder compositions which exhibit improved stability over time comprising glycopyrronium, and methods for producing the same.
International Patent Application Publication No. WO 2011/076841 discloses solution aerosol formulation suitable for administering to COPD patients by means of a pressurized metered dose inhaler, comprising glycopyrronium chloride in combination with formoterol
International Patent Application Publication No. WO2010/138868 relates to a pharmaceutical formulation comprising suspension medium comprising combination of long acting muscarinic antagonist and beta agonist to form co-suspension
There still exists a need for an effective therapeutic treatment for respiratory diseases like asthma and COPD.
SUMMARY OF THE INVENTION
The present invention relates to an inhalable fixed dose dry powder composition comprising glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt and lactose.
In an embodiment, there is provided an inhalable fixed dose dry powder composition comprising glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt and lactose; wherein said composition is free from a hydrophobic excipient.
In another embodiment, there is provided an inhalable fixed dose dry powder composition consisting of effective amounts of glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt and lactose.
In an embodiment, the present invention relates to an inhalable fixed dose dry powder composition comprising (i) a co-micronized premix consisting of glycopyrronium or its pharmaceutically acceptable salt and one part of lactose in a weight ratio of about 1 : 10 to about 1 :500 and having D90 particle size in the range of about 0.5 μπι to about 10 μπι; (ii) formoterol or its pharmaceutically acceptable salt; and (iii) another part of lactose having D90 particle size in the range of about 5 μπι to about 300 μπι; wherein said composition is free from a hydrophobic excipient. In an aspect, the weight ratio of glycopyrronium or its pharmaceutically acceptable salt to the one part of lactose in the co-micronized premix ranges from about 1 :60 to about 1 :400.
In an embodiment, the present invention relates to an inhalable fixed dose dry powder composition comprising (i) a co-micronized premix consisting of glycopyrronium or its pharmaceutically acceptable salt and one part of lactose in a weight ratio of about 1 :50 to about 1 :500 and having D9090 particle size in the range of about 0.5 μπι to about 10 μπι; (ii) formoterol or its pharmaceutically acceptable salt; and (iii) another part of lactose having D90 particle size in the range of about 5 μπι to about 300 μπι; wherein said composition is free from a hydrophobic excipient. In an aspect, the weight ratio of glycopyrronium or its pharmaceutically acceptable salt to the one part of lactose in the co-micronized premix ranges from about 1 :60 to about 1 :400.
In an embodiment, the present invention relates to an inhalable fixed dose dry powder composition comprising (i) a co-micronized premix consisting of glycopyrronium or its pharmaceutically acceptable salt and one part of lactose in a weight ratio of about 1 :50 to about 1 :500 and having D90 particle size in the range of about 0.5 μπι to about 10 μπι; (ii) formoterol or its pharmaceutically acceptable salt; and (iii) another part of lactose having D90 particle size in the range of about 5 μπι to about 200 μπι; wherein said composition is free from a hydrophobic excipient. In an aspect, the weight ratio of glycopyrronium or its pharmaceutically acceptable salt to the one part of lactose in the co-micronized premix ranges from about 1:70 to about 1:300, or from about
1: 100 to about 1:200.
In another embodiment, the present invention relates to an inhalable fixed dose dry powder composition (i) a co-micronized premix consisting of glycopyrronium or its pharmaceutically acceptable salt and one part of lactose in a weight ratio of about 1: 100 to about 1:200 and having D90 particle size in the range of about 1 μπι to about 8 μηι; (ii) formoterol or its pharmaceutically acceptable salt; and (iii) another part of lactose having
D9090 particle size in the range of about 8 μπι to about 200 μπι; wherein said composition is free from a hydrophobic excipient. In an aspect, the D90 particle size of the co- micronized premix is in the range of about 2 μπι to about 7 μπι, or about 3 μπι to about 5 μπι. In another aspect, the D90 particle size of the co-micronized premix is in the range of about 2 μπι to about 7 μπι, or about 3 μπι to about 6 μπι.
In the context of present invention, said inhalable pharmaceutical dry powder composition is free from a hydrophobic excipient.
In another embodiment, there is provided a process for preparing an inhalable fixed dose dry powder composition comprising glycopyrronium or its pharmaceutically acceptable salt and formoterol or its pharmaceutically acceptable salt, wherein said process comprises:
(a) co-micronising glycopyrronium or its pharmaceutically acceptable salt with one part of lactose to obtain a micronized premix having D90 particle size less than about 10 μπι; and;
(b) blending the co-micronized premix of step (a) and formoterol or its pharmaceutically acceptable salt with another part of lactose having D90 particle size in the range of about 5 μπι to about 200 μπι.
In another embodiment, there is provided a process for preparing an inhalable fixed dose dry powder composition comprising glycopyrronium or its pharmaceutically acceptable salt and formoterol or its pharmaceutically acceptable salt, wherein said process comprises:
(a) co-micronising glycopyrronium or its pharmaceutically acceptable salt with one part of lactose in a weight ratio of about 1:50 to about 1:500 to obtain a micronized premix having D90 particle size less than about 5 μπι; and (b) blending the co-micronized premix of step (a) and formoterol or its pharmaceutically acceptable salt with another part of lactose having D90 particle size in the range of about 8 μπι to about 200 μιη.
In another embodiment, there is provided a process for preparing an inhalable fixed dose dry powder composition comprising glycopyrronium or its pharmaceutically acceptable salt and formoterol or its pharmaceutically acceptable salt; wherein said process comprises:
(a) co-micronising glycopyrronium or its pharmaceutically acceptable salt with one part of lactose in a weight ratio of about 1 : 100 to about 1:200 to obtain a micronized premix having D90 particle size less than about 5 μπι; and;
(b) blending the co-micronized premix of step (a) and formoterol or its pharmaceutically acceptable salt with another part of lactose having D90 particle size in the range of about 8 μπι to about 200 μιη.
Preferably, the weight ratio of glycopyrronium or its pharmaceutically acceptable salt to lactose in the co-micronized premix of the present invention ranges from about 1: 10 to about 1 :500, from about 1:50 to about 1 :500, from about 1 :70 to about 1:300, more preferably from about 1 : 100 to about 1: 200.
In an embodiment of the present invention, the weight ratio of the co-micronized premix to lactose ranges froml: l to 1 :50, preferably, from 1 :5 to 1:30.
In another embodiment, there is provided an inhalable fixed dose dry powder composition comprising from about 0.01% to about 10% by weight of glycopyrronium or its pharmaceutically acceptable salt, and about 0.01% to about 10% by weight of formoterol or its pharmaceutically acceptable salt wherein the composition has fine particle mass (FPM) in the range of 1 meg to 15 meg; and wherein said composition is prepared by a method comprising:
(a) co-micronising glycopyrronium or its pharmaceutically acceptable salt with one part of lactose to obtain a micronized premix having D90 particle size less than about 5 μπι; and;
(b) blending the co-micronized premix of step (a), and formoterol or its pharmaceutically acceptable salt with another part of lactose having D90 particle size in the range of about 8 μπι to about 200 μιη. In another embodiment, there is provided an inhalable fixed dose dry powder composition comprising from about 0.01% to about 10% by weight of glycopyrronium or its pharmaceutically acceptable salt, and about 0.01% to about 10% by weight of formoterol or its pharmaceutically acceptable salt wherein the composition has total fine particle mass (FPM) in the range of 1 meg to 10 meg; and wherein said composition is prepared by a method comprising:
(a) co-micronising glycopyrronium or its pharmaceutically acceptable salt with one part of lactose to obtain a micronized premix having D90 particle size less than about 5 μπι; and;
(b) blending the co-micronized premix of step (a), and formoterol or its pharmaceutically acceptable salt with another part of lactose having D90 particle size in the range of about 8 μπι to about 200 μιη.
In another embodiment, there is provided an inhalable fixed dose dry powder composition comprising from about 0.01% to about 10% by weight of glycopyrronium or its pharmaceutically acceptable salt, and about 0.01% to about 10% by weight of formoterol or its pharmaceutically acceptable salt wherein the composition has fine particle mass (FPM) for Glycopyrronium in the range of 2.5 meg to 9 meg; and wherein said composition is prepared by a method comprising:
(a) co-micronising glycopyrronium or its pharmaceutically acceptable salt with one part of lactose to obtain a micronized premix having D90 particle size less than about 5 μπι; and;
(b) blending the co-micronized premix of step (a), and formoterol or its pharmaceutically acceptable salt with another part of lactose having D90 particle size in the range of about 8 μπι to about 300 μιη.
In another embodiment, there is provided an inhalable fixed dose dry powder composition comprising a co-micronized premix consisting of glycopyrronium or its pharmaceutically acceptable salt and lactose in a weight ratio of about 1: 100 to about 1:200; formoterol or its pharmaceutically acceptable salt and lactose wherein said premix has mean particle size of less than about 5 μπι; and said composition is free from a hydrophobic excipient; and wherein the composition has total fine particle mass in the range of 1 meg to 15 meg. In another embodiment, there is provided an inhalable fixed dose dry powder composition comprising (a) glycopyrronium bromide in an amount of 5 meg to 50 meg, (b) formoterol fumarate dihydrate in an amount of 5 meg to 50 meg and (c) lactose wherein said composition is free from magnesium stearate.
In another embodiment, there is provided an inhalable fixed dose dry powder composition comprising an effective amount of glycopyrronium or its pharmaceutically acceptable salt; formoterol or its pharmaceutically acceptable salt and lactose wherein the said composition has a Hausner ratio in the range of 1 to 2 or preferably, the Hausner ratio is in the range of 1.25 to 1.75 or more preferably, the Hausner ratio is in the range of 1.30 to 1.65.
In another embodiment, there is provided an inhalable fixed dose dry powder composition comprising an effective amount of glycopyrronium or its pharmaceutically acceptable salt; formoterol or its pharmaceutically acceptable salt and lactose wherein said composition has a Carr index in the range of 20% -45% or more preferably, the Carr index is in the range of 22%-40%.
In another embodiment, there is provided an inhalable fixed dose dry powder composition comprising an effective amount of glycopyrronium or its pharmaceutically acceptable salt; formoterol or its pharmaceutically acceptable salt and lactose; wherein said composition has a bulk density in the range of 0.45 g/mL - 0.65 g/mL or more preferably the bulk density in the range of 0.5 g/mL - 0.6 g/mL.
In another embodiment, there is provided an inhalable fixed dose dry powder composition comprising an effective amount of glycopyrronium or its pharmaceutically acceptable salt; formoterol or its pharmaceutically acceptable salt and lactose wherein said composition has a tap density in the range of 0.55 g/mL - 0.95 g/mL or more preferably the tap density in the range of 0.6 g/mL - 0.9 g/mL.
In an embodiment, the present invention relates to a method of treating respiratory disorders in a subject;, said method comprising administering by inhalation route to the subject fixed dose dry powder composition comprising effective amounts of glycopyrronium bromide, formoterol fumarate dihydrate and lactose, wherein the said composition is free from magnesium stearate. The respiratory disorder, in the context of present invention, includes but is not limited to asthma, emphysema, bronchitis, COPD, sinusitis, respiratory depression, reactive airways dysfunction syndrome (RADS), acute respiratory distress syndrome (ARDS), irritant induced asthma, occupational asthma, sensory hyper-reactivity, airway (or pulmonary) inflammation, multiple chemical sensitivity, and aid in smoking cessation therapy.
In the context of present invention, the term "asthma" includes acute asthma, chronic asthma, intermittent asthma, mild persistent asthma, moderate persistent asthma, severe persistent asthma, chronic persistent asthma, mild to moderate asthma, mild to moderate persistent asthma, mild to moderate chronic persistent asthma, allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, nocturnal asthma, bronchial asthma, exercise induced asthma, occupational asthma, seasonal asthma, silent asthma, gastroesophageal asthma, idiopathic asthma and cough variant asthma.
In an embodiment, the present invention relates to a method of treating asthma in a subject, said method comprising administering by inhalation route to the subject the dry powder composition comprising an effective amount of glycopyrronium bromide, formoterol fumarate dihydrate and lactose; wherein said composition is free from magnesium stearate.
In an embodiment, the present invention relates to a method of treating COPD in a subject, said method comprising administering by inhalation route to the subject the dry powder composition comprising an effective amount of glycopyrronium bromide, formoterol fumarate dihydrate and lactose; wherein said composition is free from magnesium stearate.
In a further embodiment, the present invention relates to use of an effective amount of glycopyrronium bromide and formoterol fumarate dihydrate in the fixed dose inhalable pharmaceutical dry powder composition of the present invention for the treatment of respiratory disorders in a subject.
In a further embodiment, the present invention relates to fixed dose inhalable pharmaceutical dry powder composition comprising an effective amount of glycopyrronium bromide and formoterol fumarate dihydrate for the treatment of respiratory disorders in a subject. DETAILED DESCRIPTION OF THE INVENTION
The terms used herein are defined as follows. If a definition set forth in the present application and a definition set forth later in a non-provisional application claiming priority from the present provisional application are in conflict, the definition in the non-provisional application shall control the meaning of the terms.
The term singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "an excipient" includes a single excipient as well as two or more different excipients, and the like.
Glycopyrrolate is a quaternary ammonium salt. Suitable counter ions are pharmaceutically acceptable counter ions including, for example, fluoride, chloride, bromide, iodide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, propionate, butyrate, lactate, citrate, tartrate, malate, maleate, succinate, benzoate, p-chlorobenzoate, diphenyl- acetate or triphenylacetate, o-hydroxybenzoate, p-hydroxybenzoate, 1- hydroxynaphthalene-2-carboxylate, 3-hydroxynaphthalene-2-carboxylate, methane- sulfonate and benzenesulfonate. A particularly preferred salt of glycopyrrolate is glycopyrronium bromide. Glycopyrrolate has two centers of asymmetry (chiral centers), and can exist in four stereoisometric forms namely (3R, 2'R)-, (3S, 2'R)-, (3R, 2'S)- and (3S, 2'S).
By "salt" or "pharmaceutically acceptable salt", it is meant those salts and esters which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit to risk ratio, and effective for their intended use.
Representative acid additions salts include the hydrochloride, furoate, hydrobromide, sulphate, bisulphate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate, succinate, tartrate, ascorbate, glucoheptonate, lactobionate, and lauryl sulphate salts. Representative alkali or alkaline earth metal salts include the sodium, calcium, potassium and magnesium salts. The term "formoterol" is used in a broad sense to include not only "formoterol" per se but also its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable esters, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable complex, pharmaceutically acceptable co-crystals etc. formoterol salts include acid addition salts such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid and p-toluenesulfonic. Preferably the formoterol salt used in the present invention is formoterol tartrate or formoterol fumarate, more preferably formoterol fumarate dihydrate.
The term "effective amount" or "therapeutically effective amount" denotes an amount of an active ingredient that, when administered to a subject for treating respiratory disorders, produces an intended therapeutic benefit in a subject. The term "active ingredient" (used interchangeably with "active" or "active substance" or "drug") as used herein includes Glycopyrronium or a pharmaceutically acceptable salt thereof.
The term "treating" or "treatment" as used herein also covers the prophylaxis, mitigation, prevention, amelioration, or suppression of a disorder modulated by the Glycopyrronium or its pharmaceutically acceptable salt in a mammal.
The term "subject" includes mammals like human and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife). Preferably, the subject is a human.
By "pharmaceutically acceptable excipients", it is meant any of the components of a pharmaceutical composition other than the actives and which are approved by regulatory authorities or are generally regarded as safe for human or animal use.
As used herein, the term "average particle size" (or synonymously, "mean particle size") refers to the distribution of particles, wherein about 50 volume percent of all the particles measured have a size less than the defined average particle size value and about 50 volume percent of all measurable particles measured have a particle size greater than the defined average particle size value. This can be identified by the term "D50" or "d (0.5)". Similarly, D90 value relates to about 90 volume percent of all the particles measured have a size less than the defined particle size value (also referred to as "D90 particle size'). The particle size can be measured using various techniques like laser diffraction, photon correlation spectroscopy (PCS) and Coulter's principle.
The term "co-micronisation" refers to milling or micronisation of the active ingredient and lactose together in suitable mill to obtain micronised mixture of active ingredient and lactose. The mixture of active ingredient and lactose after co- micronisation process can be called as co-micronised premix of active ingredient and lactose. Jet mill, Air jet mill, Ball mill and the like can be used for the milling purpose. Preferably Air Jet Mill may be used for co-micronisation.
The fine particle mass (FPM) test is normally conducted using a validated multistage impactor or impinger method, or a suitably validated alternative. It is normally considered acceptable to set upper and lower limits on the results of pooled stages corresponding to a particle size distribution of less than 5 micrometer, although alternative limits may be found acceptable with adequate justification. The drug mass should be reported rather than the percentage of emitted dose (or other derived parameter).
The Mass Median Aerodynamic Diameter (MMAD) is defined as the diameter at which 50% of the particles by mass are larger and 50% are smaller.
The Carr index and Hausner ratio are frequently used in as an indication of the flowability of a powder. The Carr index and Hausner ratio can be determined using Tap Density Apparatus. The bulk density and tap density of the powder composition can be determined by Tap density apparatus.
The pharmaceutical composition in the above embodiments may optionally comprise one or more pharmaceutically acceptable excipients.
The inhalable pharmaceutical dry powder composition of the present invention may contain one or more pharmaceutically acceptable excipients. Examples of such excipients include but are not limited to diluents, solvents, and the like.
The pharmaceutically acceptable diluent suitable for use in the invention is selected from lactose, mannitol, sucrose, trehalose, cyclodextrin, or mixtures thereof. Preferably, the pharmaceutically acceptable diluent is lactose. Various grade of lactose are available for use in dry powder compositions are selected from Respitose SV010, Respitose® SV003, Respitose® ML006, InhaLac 70, InhaLac 230, Lactose Monohydrate Inhalation 40M, Lactose Anhydrous 120M, Lactohale® 300, and the like.
Examples of solvents include water, propylene glycol, ether, petroleum ether, alcohols, e.g. methanol, ethanol, isopropyl alcohol and higher alcohols; alkanes, e.g. pentane, hexane and heptane; ketones, e.g. acetone and methyl ethyl ketone; and the like and mixtures thereof.
The process of preparing an inhalable pharmaceutical dry powder composition comprising glycopyrronium or its pharmaceutically acceptable salts, wherein said process comprises:
(a) co-micronising glycopyrronium or its pharmaceutically acceptable salts with one part of lactose to obtain a micronized premix having D90 particle size less than about 5 μπι; and,
(b) blending the co-micronized premix of step (a); formoterol or its pharmaceutically acceptable salt with another part of lactose having D90 particle size in the range of about 8 μπι to about 200 μιη.
The powder composition may be further be filled into a capsule for inhalation or may be processed into a lightly compressed tablet or powder agglomeration which can be easily crushed to obtain a powder for inhalation. Alternately, the composition can be filled, either as discrete dosage units, in a blister or a sachet or in a reservoir for multiple uses.
In an embodiment, there is provided an inhalable fixed dose dry powder composition comprising glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt and lactose; wherein said composition is free from a hydrophobic excipient.
In another embodiment, the co-micronization followed by blending is preferred over simple blending process.
In another embodiment, there is provided an inhalable fixed dose dry powder composition consisting of an effective amount of glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt and lactose. In an embodiment, the present invention relates to an inhalable fixed dose dry powder composition comprising (i) a co-micronized premix consisting of glycopyrronium or its pharmaceutically acceptable salt and one part of lactose in a weight ratio of about 1 : 10 to about 1 :500 and having D90 particle size in the range of about 0.5 μπι to about 10 μπι; (ii) formoterol or its pharmaceutically acceptable salt; and (iii) another part of lactose having D90 particle size in the range of about 5 μπι to about 300 μπι; wherein said composition is free from a hydrophobic excipient. In an aspect, the weight ratio of glycopyrronium or its pharmaceutically acceptable salt to the one part of lactose in the co-micronized premix ranges from about 1 :60 to about 1 :400.
In an embodiment, the present invention relates to an inhalable fixed dose dry powder composition comprising; (i) a co-micronized premix consisting of glycopyrronium or its pharmaceutically acceptable salt and one part of lactose in a weight ratio of about 1 :50 to about 1 :500 and having D90 particle size in the range of about 0.5 μπι to about 10 μπι; (ii) formoterol or its pharmaceutically acceptable salt; and (iii) another part of lactose having D90 particle size in the range of about 5 μπι to about 200 μπι; wherein said composition is free from a hydrophobic excipient. In an aspect, the weight ratio of glycopyrronium or its pharmaceutically acceptable salt to the one part of lactose in the co-micronized premix ranges from about 1 :70 to about 1 :300, or from about 1 : 100 to about 1 :200.
In another embodiment, the present invention relates to an inhalable fixed dose dry powder composition (i) a co-micronized premix consisting of glycopyrronium or its pharmaceutically acceptable salt and one part of lactose in a weight ratio of about 1 : 100 to about 1 :200 and having D90 particle size in the range of about 1 μπι to about 8 μηι; (ii) formoterol or its pharmaceutically acceptable salt; and (iii) another part of lactose having D90 particle size in the range of about 8 μπι to about 200 μπι; wherein said composition is free from a hydrophobic excipient. In an aspect, the D90 particle size of the co-micronized premix is in the range of about 2 μπι to about 7 μπι, or about 3 μπι to about 5 μπι.
In the context of present invention, said inhalable pharmaceutical dry powder composition is free from a hydrophobic excipient.
In an embodiment, the present invention relates to an inhalable fixed dose dry powder composition comprising (i) a co-micronized premix consisting of glycopyrronium or its pharmaceutically acceptable salt and one part of lactose in a weight ratio of about 1 :50 to about 1 :500 and having D90 particle size in the range of about 0.5 μπι to about 10 μπι; (ii) formoterol or its pharmaceutically acceptable salt; and (iii) another part of lactose having D90 particle size in the range of about 5 μπι to about 300 μπι; wherein said composition is free from a hydrophobic excipient. In an aspect, the weight ratio of glycopyrronium or its pharmaceutically acceptable salt to the one part of lactose in the co-micronized premix ranges from about 1 :60 to about 1 :400.
In another embodiment, there is provided a process for preparing an inhalable fixed dose dry powder composition comprising glycopyrronium or its pharmaceutically acceptable salt and formoterol or its pharmaceutically acceptable salt, wherein said process comprises:
(a) co-micronising glycopyrronium or its pharmaceutically acceptable salt with one part of lactose to obtain a micronized premix having D90 particle size less than about 10 μπι; and;
(b) blending the co-micronized premix of step (a) and formoterol or its pharmaceutically acceptable salt with another part of lactose having D90 particle size in the range of about 5 μπι to about 200 μπι.
In another embodiment, there is provided a process for preparing an inhalable fixed dose dry powder composition comprising glycopyrronium or its pharmaceutically acceptable salt and formoterol or its pharmaceutically acceptable salt, wherein said process comprises:
(a) co-micronising glycopyrronium or its pharmaceutically acceptable salt with one part of lactose in a weight ratio of about 1 :50 to about 1 :500 to obtain a micronized premix having D90 particle size less than about 5 μπι; and
(b) blending the co-micronized premix of step (a) and formoterol or its pharmaceutically acceptable salt with another part of lactose having D90 particle size in the range of about 8 μπι to about 200 μιη.
In another embodiment, there is provided a process for preparing an inhalable fixed dose dry powder composition comprising glycopyrronium or its pharmaceutically acceptable salt and formoterol or its pharmaceutically acceptable salt; wherein said process comprises: (a) co-micronising glycopyrronium or its pharmaceutically acceptable salt with one part of lactose in a weight ratio of about 1 : 100 to about 1 :200 to obtain a micronized premix having D90 particle size less than about 5 μπι; and;
(b) blending the co-micronized premix of step (a) and formoterol or its pharmaceutically acceptable salt with another part of lactose having D90 particle size in the range of about 8 μπι to about 200 μιη.
Preferably, the weight ratio of glycopyrronium or its pharmaceutically acceptable salt to lactose in the co-micronized premix of the present invention ranges from about 1 : 10 to about 1 :500, 1 :50 to about 1 :500, from about 1 :70 to about 1 :300, more preferably from about 1 : 100 to about 1 : 200.
In an embodiment of the present invention, the weight ratio of the co-micronized premix to lactose ranges froml : l to 1 :50, preferably, from 1 :5 to 1 :30.
In another embodiment, there is provided an inhalable fixed dose dry powder composition comprising from about 0.01 % to about 10% by weight of glycopyrronium or its pharmaceutically acceptable salt, and about 0.01 % to about 10% by weight of formoterol or its pharmaceutically acceptable salt wherein the composition has fine particle mass (FPM) in the range of 1 meg to 15 meg; and wherein said composition is prepared by a method comprising:
(a) co-micronising glycopyrronium or its pharmaceutically acceptable salt with one part of lactose to obtain a micronized premix having D90 particle size less than about 5 μπι; and;
(b) blending the co-micronized premix of step (a), and formoterol or its pharmaceutically acceptable salt with another part of lactose having D90 particle size in the range of about 8 μπι to about 200 μιη.
In another embodiment, there is provided an inhalable fixed dose dry powder composition comprising from about 0.01 % to about 10% by weight of glycopyrronium or its pharmaceutically acceptable salt, and about 0.01 % to about 10% by weight of formoterol or its pharmaceutically acceptable salt wherein the composition has total fine particle mass (FPM) in the range of 1 meg to 10 meg; and wherein said composition is prepared by a method comprising: (a) co-micronising glycopyrronium or its pharmaceutically acceptable salt with one part of lactose to obtain a micronized premix having D90 particle size less than about 5 μπι; and;
(b) blending the co-micronized premix of step (a), and formoterol or its pharmaceutically acceptable salt with another part of lactose having D90 particle size in the range of about 8 μπι to about 200 μιη.
In another embodiment, there is provided an inhalable fixed dose dry powder composition comprising from about 0.01% to about 10% by weight of glycopyrronium or its pharmaceutically acceptable salt, and about 0.01% to about 10% by weight of formoterol or its pharmaceutically acceptable salt wherein the composition has fine particle mass (FPM) for Glycopyrronium in the range of 2.5 meg to 9 meg; and wherein said composition is prepared by a method comprising:
(a) co-micronising glycopyrronium or its pharmaceutically acceptable salt with one part of lactose to obtain a micronized premix having D90 particle size less than about 5 μπι; and;
(b) blending the co-micronized premix of step (a), and formoterol or its pharmaceutically acceptable salt with another part of lactose having D90 particle size in the range of about 8 μπι to about 300 μιη.
In another embodiment, there is provided an inhalable fixed dose dry powder composition comprising a co-micronized premix consisting of glycopyrronium or its pharmaceutically acceptable salt and lactose in a weight ratio of about 1: 100 to about 1:200; formoterol or its pharmaceutically acceptable salt and lactose wherein said premix has mean particle size of less than about 5 μπι; and said composition is free from a hydrophobic excipient; and wherein the composition has total fine particle mass in the range of 1 meg to 10 meg.
In another embodiment, there is provided an inhalable fixed dose dry powder composition comprising (a) glycopyrronium bromide in an amount of 5 meg to 50 meg, (b) formoterol fumarate dihydrate in an amount of 5 meg to 50 meg and (c) lactose wherein said composition is free from magnesium stearate.
In another embodiment, there is provided an inhalable fixed dose dry powder composition comprising an effective amount of glycopyrronium or its pharmaceutically acceptable salt, formoterol or its pharmaceutically acceptable salt and lactose wherein the said composition has a Hausner ratio in the range of 1 to 2 or preferably, the Hausner ratio is in the range of 1.25 to 1.75 or more preferably, the Hausner ratio is in the range of 1.30 to 1.65.
In another embodiment, there is provided an inhalable fixed dose dry powder composition comprising an effective amount of glycopyrronium or its pharmaceutically acceptable salt; formoterol or its pharmaceutically acceptable salt and lactose wherein said composition has a Carr index in the range of 20% -45% or more preferably, the Carr index is in the range of 22%-40%.
In another embodiment, there is provided an inhalable fixed dose dry powder composition comprising an effective amount of glycopyrronium or its pharmaceutically acceptable salt; formoterol or its pharmaceutically acceptable salt and lactose wherein said composition has a bulk density in the range of 0.45 g/mL - 0.65 g/mL or more preferably the bulk density in the range of 0.5 g/mL - 0.6 g/mL.
In another embodiment, there is provided an inhalable fixed dose dry powder composition comprising an effective amount of glycopyrronium or its pharmaceutically acceptable salt; formoterol or its pharmaceutically acceptable salt and lactose wherein said composition has a tap density in the range of 0.55 g/mL - 0.95 g/mL or more preferably the tap density in the range of 0.6 g/mL - 0.9 g/mL.
In an embodiment, there is provided an inhalable fixed dose dry powder composition comprising from about 0.01% to about 10%, preferably from about 0.02% to about 5%, more preferably from about 0.03% to about 4% by weight of glycopyrronium or its pharmaceutically acceptable salt, and about 0.01% to about 10% by weight of formoterol or its pharmaceutically acceptable salt
In an embodiment, the present invention relates to a method of treating respiratory disorders in a subject, said method comprising administering by inhalation route to the subject fixed dose dry powder composition comprising effective amounts of glycopyrronium bromide, formoterol fumarate dihydrate and lactose, wherein said composition is free from magnesium stearate.
The respiratory disorder, in the context of present invention, includes but is not limited to asthma, emphysema, bronchitis, COPD, sinusitis, respiratory depression, reactive airways dysfunction syndrome (RADS), acute respiratory distress syndrome (ARDS), irritant induced asthma, occupational asthma, sensory hyper-reactivity, airway (or pulmonary) inflammation, multiple chemical sensitivity, and aid in smoking cessation therapy.
In the context of present invention, the term "asthma" includes acute asthma, chronic asthma, intermittent asthma, mild persistent asthma, moderate persistent asthma, severe persistent asthma, chronic persistent asthma, mild to moderate asthma, mild to moderate persistent asthma, mild to moderate chronic persistent asthma, allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, nocturnal asthma, bronchial asthma, exercise induced asthma, occupational asthma, seasonal asthma, silent asthma, gastroesophageal asthma, idiopathic asthma and cough variant asthma.
In an embodiment, the present invention relates to a method of treating asthma in a subject, said method comprising administering by inhalation route to the subject the dry powder composition comprising an effective amount of glycopyrronium bromide, formoterol fumarate dihydrate and lactose; wherein said composition is free from magnesium stearate.
In an embodiment, the present invention relates to a method of treating COPD in a subject, said method comprising administering by inhalation route to the subject the dry powder composition comprising an effective amount of glycopyrronium bromide, formoterol fumarate dihydrate and lactose; wherein said composition is free from magnesium stearate.
In a further embodiment, the present invention relates to use of an effective amount of glycopyrronium bromide; formoterol fumarate dihydrate in the inhalable pharmaceutical dry powder composition of the present invention for the treatment of respiratory disorders in a subject.
In a further embodiment, the present invention relates to an inhalable dry powder composition comprising an effective amount of glycopyrronium bromide; formoterol fumarate dihydrate for the treatment of respiratory disorders in a subject.
The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention. EXAMPLES
EXAMPLE 1:
(a) Premix Preparation:
Figure imgf000021_0001
Manufacturing process:
1. Glycopyrrolate and lactose were mixed thoroughly.
2. The blend from Stepl was micronised in Air jet mill till the D90 particle size is in the range of about 3 μπι to about 5 μπι. (b) Blending:
Figure imgf000021_0002
Manufacturing process:
1. Glycopyrrolate micronised premix; formoterol fumarate dihydrate and fine grade lactose were sifted and then mixed in a suitable blender.
2. The blend of step 1 was sifted with a part of coarse grade lactose monohydrate and then mixed in a suitable blender. 3. The blend of step 2 was sifted with remaining part of lactose and then mixed in a suitable blender.
4. The blend of step 3 was filled in a capsule.
Stability study of Example 1
Figure imgf000022_0001
EXAMPLE 2:
(a) Premix Preparation:
Figure imgf000022_0002
Manufacturing process:
1. Lactose monohydrate was divided in two parts.
2. Glycopyrrolate was mixed with first part of Lactose Monohydrate (Respitose SVOlO), and sifted through #60 sieve and blended.
3. Second part of Lactose Monohydrate (Respitose SVOlO), was added to blend from Step 2 and sifted through #60 sieve and blended.
4. The blend from Step-3 was micronised in Air jet mill till the D90 particle size is in the range of about 3 μπι to about 6 μπι. b. Final blend:-
Figure imgf000023_0001
Compositions as per strategy III
mg/unit
# Ingredients Comp Comp Comp Comp Comp
I II III IV V
Glycopyrronium
1 3.000 3.000 3.000 3.000 3.000 micronised blend
Formoterol Fumarate
2 0.012 0.012 0.012 0.012 0.012 Dihydrate
Lactose Monohydrate
3 - 2.488 6.988 8.488 6.988 (Respitose ML006)
Lactose Monohydrate
4 21.988 19.500 15.000 13.500 - (Respitose SV010
Lactose Monohydrate
5 - - - - 15.000 (Inhalac 70)
Net weight 25.000 25.000 25.000 25.000 25.000
6 HPMC Capsule 50.000 50.000 50.000 50.000 50.000
Total weight of filled capsule 75.000 75.000 75.000 75.000 75.000
Figure imgf000024_0001
Compositions as per strategy V
mg/unit
# Ingredients Comp Comp Comp Comp
Comp I
II III IV V
Glycopyrronium
1 0.750 0.750 0.750 0.750 0.750 micronised blend
Formoterol Fumarate
2 0.012 0.012 0.012 0.012 0.012 Dihydrate
Lactose Monohydrate
3 - 3.488 6.988 9.488 6.988 (Respitose ML006)
Lactose Monohydrate
4 24.238 20.750 17.250 14.750 - (Respitose SV010
Lactose Monohydrate
5 - - - - 17.250 (Inhalac 70)
Net weight 25.000 25.000 25.000 25.000 25.000
6 HPMC Capsule 50.000 50.000 50.000 50.000 50.000
Total weight of filled capsule 75.000 75.000 75.000 75.000 75.000
Manufacturing process:
1. Glycopyrrolate micronised premix; formoterol fumarate dihydrate and fine grade lactose (Respitose ML006) were sifted and then mixed in a suitable blender.
2. The blend of step 1 was sifted with a part of coarse grade lactose monohydrate and then mixed in a suitable blender.
3. The blend of step 2 was sifted with remaining part of lactose and then mixed in a suitable blender.
4. The blend of step 3 was filled in a capsule.
Stability study of Example 2 (Strategy II, Comp III)
Figure imgf000025_0001
Figure imgf000026_0001
Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and application of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above.
All publications, patents, and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference.

Claims

We Claim:
1. An inhalable fixed dose dry powder composition comprising (i) a co-micronized premix consisting of glycopyrronium or its pharmaceutically acceptable salt and one part of lactose in a weight ratio of about 1 : 10 to about 1 :500 and having D90 particle size in the range of about 0.5 μπι to about 10 μπι; (ii) formoterol or its
pharmaceutically acceptable salt; and (iii) another part of lactose having D90 particle size in the range of about 5 μπι to about 300 μπι; wherein said composition is free from a hydrophobic excipient.
2. The dry powder composition of claim 1 , wherein the said composition is free from magnesium stearate.
3. The dry powder composition of claim 1, wherein weight ratio of glycopyrronium or its salt to the one part of lactose in the co-micronized premix ranges from about 1 :60 to about 1 :400.
4. The dry powder composition of claim 1 , wherein the D90 particle size of the co- micronized premix is in the range of about 2 μπι to about 7 μπι, or about 3 μπι to about 6 μπι.
5. The dry powder composition of claim 1, wherein the composition comprises of about 0.01 % to about 10% by weight of glycopyrronium or its salt.
6. The dry powder composition of claim 1 , wherein the composition has fine particle mass in the range of 1 meg to 15 meg.
7. The dry powder composition of claim 1, wherein said composition has Hausner ratio in the range of 1 to 2 or preferably Hausner ratio is in the range of 1.25 to 1.75.
8. The dry powder composition of claim 1, wherin the said composition has Carr index in the range of 20% -45% or more preferably the Carr index is in the range of 22%- 40%.
9. The dry powder composition of claim 1, wherin the said composition has bulk density in the range of 0.45 g/mL - 0.65 g/mL or more preferably bulk density in the range of 0.5 g/mL - 0.6 g/mL.
10. The dry powder composition of claim 1, wherin the said composition has tap density in the range of 0.65 g/mL - 0.95 g/mL or more preferably tap density in the range of 0.7 g/mL - 0.9 g/mL.
11. A process for preparing an inhalable fixed dose dry powder composition comprising from about 0.01% to about 10% by weight of glycopyrronium or its pharmaceutically acceptable salt, and about 0.01% to about 10% by weight of formoterol or its pharmaceutically acceptable salt wherein the composition has fine particle mass (FPM) in the range of 1. meg to 15 meg; and wherein said composition is prepared by a method comprising:
(a) co-micronising glycopyrronium or its pharmaceutically acceptable salt with
one part of lactose to obtain a micronized premix having D90 particle size less than about 5 μπι; and;
(b) blending the co-micronized premix of step (a), and formoterol or its
pharmaceutically acceptable salt with another part of lactose having D90 particle size in the range of about 8 μπι to about 300 μιη, wherein said composition is free from a hydrophobic excipient.
12. A method of treating respiratory disorders in a subject, said method comprising
administering by inhalation route to the subject the dry powder composition comprising an effective amount of glycopyrronium bromide, formoterol fumarate dihydrate and lactose, wherein said composition is free from magnesium stearate.
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Publication number Priority date Publication date Assignee Title
WO2020084549A1 (en) * 2018-10-25 2020-04-30 Glenmark Specialty S.A. Nebulization composition comprising glycopyrrolate and formoterol
WO2021070150A1 (en) * 2019-10-11 2021-04-15 Glenmark Specialty S.A. An inhalable dry powder composition for pulmonary diseases

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2347856A1 (en) * 1998-11-13 2000-05-25 Jago Research Ag Dry powder for inhalation
WO2005074900A2 (en) * 2004-02-06 2005-08-18 Meda Pharma Gmbh & Co. Kg NOVEL COMBINATION OF ANTICHOLINERGIC AND β MIMETICS FOR THE TREATMENT OF RESPIRATORY DISEASES

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2347856A1 (en) * 1998-11-13 2000-05-25 Jago Research Ag Dry powder for inhalation
WO2005074900A2 (en) * 2004-02-06 2005-08-18 Meda Pharma Gmbh & Co. Kg NOVEL COMBINATION OF ANTICHOLINERGIC AND β MIMETICS FOR THE TREATMENT OF RESPIRATORY DISEASES

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020084549A1 (en) * 2018-10-25 2020-04-30 Glenmark Specialty S.A. Nebulization composition comprising glycopyrrolate and formoterol
WO2021070150A1 (en) * 2019-10-11 2021-04-15 Glenmark Specialty S.A. An inhalable dry powder composition for pulmonary diseases

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